TY - JOUR
T1 - Influence of peptidase inhibitors on the apparent agonist potency of delta selective opioid peptides in vitro
AU - Kramer, Thomas H.
AU - Toth, Geza
AU - Haaseth, Ronald C.
AU - Matsunaga, Terry O.
AU - Davis, Peg
AU - Hruby, Victor J.
AU - Burks, Thomas F.
N1 - Funding Information:
This work was supported by USPHS grants DA02163, DA06284, NS19972 and DA04248.
PY - 1991
Y1 - 1991
N2 - Several peptides of diverse structure, reported to possess high affinity and selectivity for the δ opioid receptor, were studied using the mouse isolated vas deferens preparation to determine the effect of peptidase inhibition on their apparent potency. The peptides evaluated included [Leu5]enkephalin, the cyclic enkephalin analogs [D-Pen2, D-Pen5] enkephalin (DPDPE) and [D-Pen2, p-F-Phe4, D-Pen5]enkephalin (F-DPDPE), the linear enkephalin analogs [D-Ala2, D-Leu5]enkephalin (DADLE) and [D-Ser2(O-tBu), Leu5, Thr6]enkephalin (DSTBULET), and the naturally occurring amphibian peptides Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (dermenkephalin), Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 (deltorphin I) and Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 (deltorphin II). Concentration-response curves were determined for each peptide in the absence and presence of a combination of the peptidase-inhibiting agents bacitracin, bestatin, and captopril. A wide range of potencies was observed, both in the control state and in the presence of peptidase inhibition. The synthetic enkephalin analogs demonstrated small increases in potency with peptidase inhibition (no increase in the case of DPDPE), whereas the naturally occurring peptides were markedly increased in potency, up to as much as 123-fold for dermenkephalin. In the presence of peptidase inhibition, deltorphin II was the most potent peptide tested (IC50 = 1.13 X 10-10 molar), and as such is the most potent delta opioid agonist reported to date. Stability to metabolism must be considered in the design and evaluation of in vitro experiments using peptides of this type.
AB - Several peptides of diverse structure, reported to possess high affinity and selectivity for the δ opioid receptor, were studied using the mouse isolated vas deferens preparation to determine the effect of peptidase inhibition on their apparent potency. The peptides evaluated included [Leu5]enkephalin, the cyclic enkephalin analogs [D-Pen2, D-Pen5] enkephalin (DPDPE) and [D-Pen2, p-F-Phe4, D-Pen5]enkephalin (F-DPDPE), the linear enkephalin analogs [D-Ala2, D-Leu5]enkephalin (DADLE) and [D-Ser2(O-tBu), Leu5, Thr6]enkephalin (DSTBULET), and the naturally occurring amphibian peptides Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (dermenkephalin), Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 (deltorphin I) and Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 (deltorphin II). Concentration-response curves were determined for each peptide in the absence and presence of a combination of the peptidase-inhibiting agents bacitracin, bestatin, and captopril. A wide range of potencies was observed, both in the control state and in the presence of peptidase inhibition. The synthetic enkephalin analogs demonstrated small increases in potency with peptidase inhibition (no increase in the case of DPDPE), whereas the naturally occurring peptides were markedly increased in potency, up to as much as 123-fold for dermenkephalin. In the presence of peptidase inhibition, deltorphin II was the most potent peptide tested (IC50 = 1.13 X 10-10 molar), and as such is the most potent delta opioid agonist reported to date. Stability to metabolism must be considered in the design and evaluation of in vitro experiments using peptides of this type.
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U2 - 10.1016/0024-3205(91)90034-9
DO - 10.1016/0024-3205(91)90034-9
M3 - Article
C2 - 1847736
AN - SCOPUS:0026023804
SN - 0024-3205
VL - 48
SP - 881
EP - 886
JO - Life Sciences
JF - Life Sciences
IS - 9
ER -